Aliphatic sulphonate salts of localanesthetic organic bases



Patented Nov. 10, 1942 UNITED STATES PATENT OFFICE ALIPHATIC SULPHONATESALTS OF LOCAL- ANESTHETIC ORGANIC BASES Horace A. Shonle, Indianapolis,

Eli Lilly and Company,

poration of Indiana Ind., assignor to Indianapolis, Ind., a cor- NoDrawing. Application August 19, 1940, Serial No. 353,250

4 Claims. (01. 260-472) The present application is a continuation inpart of my co-pending application Serial No. 156,938, filed August 2,1937.

It is the object of my present invention to produce certain newaliphatic sulphonates of localanesthetic organic bases, to obtainproducts which are sufficiently stable,-are water-soluble, and havegreater lipoid solubility than have the known water-soluble salts ofsuch organic bases. The local-anesthetic organic bases-organic baseswhich have local anesthetic action-of which I produce aliphaticsulphonates are in the class containing the following: V

The first seven of these local-anesthetic organic bases arelocal-anesthetic esters of a nitrogenous alcohol and a benzoic acid oftheclass consisting of benzoic acid and p-aminobenzoic acid.

carbon group as has just been defined and contains a carbon atom that isdirectly joined to the sulphur atom of the sulphonic acid group. Amongsuch aliphatic groups may be mentioned the following: butyl, amyl,hexyl, heptyl, octyl, nonyl, lauryl, myristyl, cetyl, stearyl, andoleyl.

The aliphatic sulphonic acids of my invention thus differ from thecompounds which are sometimes called mineral oil sulphonic acids; forthose so-called mineral oil sulphonic acids are complex mixtures ofcompounds having formulas I have discovered that local-anesthetic oranic 1 bases willreact with certain aliphatic sulphonic acids to producetherapeutically effective aliphatic sulphonates which also havelocal-anesthetic action, and which in many cases have certain advantagesover the known salts of these bases, as 3 for instance by reason ofdecreased toxicity, and/or lengthened action, and/oreifectiveness insmaller dosages, and combined stability, watersolubility, and greaterlipoid-solubility than known Water-soluble salts.

The aliphatic sulfonic acids which I have found effective for this arethose in which there is an aliphatic substituent having at least fourbut not to exceed eighteen carbon atoms. This aliphatic substituent maybe either primary straight-chain or primary branched-chain or secondary,and either saturated or unsaturated. In general, by the term aliphaticsulfonic acid I mean one which is represented by the following formula:R:S[|OH in which R represents such an aliphatic hydrowhich have neverbeen satisfactorily demonstrated, and are probably mixtures of esters ofsulphuric acid, rather than derivatives of true sulphonic acid, in thatin their structure an oxygen atom almost certainly intervenes betweenthe sillphur atom and the aliphatic group, and in any case they are atbest a group of unknown things mixed together.

In making these new aliphatic sulphonates, I first prepare the desiredaliphatic sulphonic acid. The various aliphatic sulphonic acids may beprepared by general methods described in the literature. For instance,see:

Annalen, vol. 148, p. 90, Strecker,

Annalen, vol. 148, p. 96, Bender,

Jour. Am. Chem. Soc., vol. 55, p. 1091, Noller and Gordon, and

Jour. Am. Chem. Soc., vol. 57, p. 570, Read and fIartar.

After the desired aliphatic sulphonic acid is obtained, it may be causedto react, in solution in a suitable solvent, with the desiredlocalanesthetic organic base, to produce the desired aliphaticsulphonate. These local-anesthetic organic bases all contain a'trivalentnitrogen atom. The reaction may be represented in general as follows:

in which R has the same significance as before, and R R and R representhydrogen atoms or organic radicals which are united to the nitrogen atomin the initial local-anesthetic organic base and at least one of whichis an organic radical. The following are some examples of my process,and of the product obtained thereby.

Example 1.n-Hexyl sulphonic acid, and procaine, are dissolved inseparate portions of ethyl ether, and the two ethereal solutions are puttogether, in the cold. As an example, dissolve 9.44grams (0.04 mole) ofprocain in about 200 cc. of the ether, and 9.05 grams (slightly morethan a molecular equivalent) of n-hexyl sulphonic acid in about 100 cc.of the ether, and gradually add the latter to the former, preferablywith stirring and cooling. Reaction occurs, and the desired procainen-hexyl sulphonate precipitates. This precipitate may be suitablyseparated, as by filtration and decantation, and purified byrecrystallizationas by dissolving it in a minimum amount of hotisopropyl or other suitable alcohol, and then chilling to producecrystals. These crystals of procainen-hexyi sulphonate are hydroscopic,and melt at about 8-87 C., uncorrected.

Example 2.Instead of using n hexyl sulphonic acid as in Example 1, I mayuse any of the following sulphonic acids, in amounts substantiallymolecularly equivalent to the amountof n-hexyl sulphonic acid given inExample 1:

n-Butyl sulphonic acid, l-methyl-butyl sulphonic acid, n-I-Iexylsulphonic acid, l-methyl-pentyl sulphonic acid, 1,3-dimethyl-butylsulphonic acid, Z-ethyl-butyl sulphonic acid, n-Heptyl sulphonic acid,2,4-dimethy1-pentyl sulphonic acid, I-methyl-heptyl sulphonic acid,2-ethyl-hexyl. sulphonic acid, n-Nonyl sulphonic acid,

Lauryl sulphonic acid,

Myristyl sulphonic acid,

Cetyl sulphonic acid,

Stearyl sulphonic acid, and

Oleyl sulphonic acid.

These sulphonic acids may all bemade, by known process,.withsodiumsulphiteand the respectively corresponding bromides or chlorides.

The procaine salts of these substituted sulphonic acids are sometimesobtained as solids, andsometimes; obtained as viscous syrups. They aresolubleinmethyl, ethyl, and isopropyl alcohol, more soluble in ,water,somewhat-soluble in oils, and relatively, insoluble in ether.

The following are examples of. these procaine aliphatic sulphonatesProcaine n-butyl. sulphonate,

Melts at about 121 to 122 C., uncorrected.

Procaine n-amylsulp-honate,

Melts at about 106.5 to 107.5 C. Procaine l-methyl-butyl sulphonate,

Obtained as a syrup.

' Procaine Z-ethyl-butyl sulphonate,

Melts at about 118 to 119.'5F"C. Procaine n-heptyl sulphonate,

Obtained as a syrup. Procaine 2,4-dimethyl-pentyl sulphonate,

Melts at about 70'72 C. Procaine l-methyl-heptyl sulphonate,

Melts atabout 76-978? C., Procaine myristyl sulphonate,

Melts at about 86-90" C. Procaine lauryl sulphonate,

Obtained as whitish crystals.

molecular proportion of h-heiiyl sulphonic acid. I then pour theethereal solution of the sulphonic acid slowly with stirring into theethereal solution of the 'y-[Z-rnethyl-piperidino]-propyl benzoate.Reaction occurs between the "y- [2-methylpiperidinol-propyl benzoate andthe n-hexyl sulphonic acid, and the desired 'y-[2-rnethyl-piperidino]-prop-yl-benZoate-n-hexyl sulphonate which is formed separates outto form a sticky precipitate. This is separated from the supernatantliquid and washed many times with ether. It is then dried under vacuo,forming a viscous syrup.

Example 4.-Instead of using n-hexyl sulphonic acid-asin Example 3, I mayuse n-nonyl sulphonic acid to react with the-EZ-methyl-piperidinol-propyl benzoate. This also produces a sticky.precipitate, of -l2-methyl-piperidinolpropyl benzoate-n-nonylsulphonate.

Example 5.-Instead of using procaine or -[2- methyl-piperidinol-propylbenzoate as the organic base, I may use cocaine; grams of cocaine maybedissolved in.100 cc; of anhydrous ether. This may bechilled .inan icebath, and to it is added slowly with stirring, 1

gram of n-amyl sulphonic acid dissolved in 20. cc.-

of anhydrous-ether. is cocaine -namyl sulphonate. arated, andrecrystallized in a solution of alcohol and ether, to obtain whitishcrystalswhich are hydroscopic and Water-soluble.

Example 6.-Instead of using procaine,- 'y-f2- methyl-piperidinol-propylbenzoate, or cocaine, I may usep-aminobenzoyl-dimethytlaminomethylbutanol. ,Idissolve one molecularpropor tion of p-aminobenzoyl dimethtylamino-methylbutanol in ether,cool this solution; and, add to it slowly, with stirring, more thanamolecularpro- A precipitate forms, which portion of n-hexylisulphonic.acid 'dissolvediin ether. A reaction occurs, and thep-aminob'enzoyl-dimethylamino-methylbutanol-n hexyl sulphonate separatesout, either .in' syrupy'form" or by careful manipulation asaynon-crystalline solid.

Example 7'.Instead ofiusing" the'local-anesthetic organic basesspecifically namedin' Examples. l to. 6inclusive-,xother.local-anesthetic organic bases. may be: used astheorganic :base: as has been. indicated: in .the' lists... already .given.These are. caused. tor reactwithtthe' desired'rali-i phatic sulphonicacids-in .the general manner I of Examples 1-6, with the aliphatic:sulphoniczacid H in solutioninanhydrous'ether; and. with the local-anesthetic organic base alsozin :SOILltiOllf in ether. The areaction.between the: aliphatic .sulphonicacidiand the localeanestheticiorganicbase produces precipitates," sometimes asisolidsl and sometimes. as.viscous ;syrups, which; are. readily separable fromtthe supernatantliquid; astby filtration or decantation. Among the aliphatic sulphonatesthus-"obtain able are those. of the followinglocal-anesthetic organicbases: I

Monoisobutylaminoethyl p-aminobenzoate,

p-Aminobenzoyl- -di-n-butylaminopropanol, I

p -Aminobenzoyl-,2-2-dimethyl"- 3 diethylaminopropanol,

Piperi'dinopropanediol-diephenylurethane,

2-butyloxyquinolinecar'boxylic acid-A-diethyleth ylene-diamide, and

-Diethylaminopropylcinnamate.

These aliphatic sulphonates of ocal anesthetic bases are in generaleither white or whitish solids, or viscous syrups; and are solubleinwater, and relatively insoluble in ether. .Those which are Forexample, 2

This solid is sepobtained in solid form may be purified byrecrystallization, in a. manner already indicated for other aliphaticsulphonates.

These aliphatic sulphonates of local-anesthetic organic bases all havelocal-anesthetic actions, corresponding in general to the actions of thelocal-anesthetic organic bases from which they are derived.

I claim as my invention:

1. A local-anesthetic salt of an aliphatic sulphonic acid which has theformula:

i 0 in which R represents an aliphatic hydrocarbon substituent which hasbetween four and eighteen carbon atoms and is of the class consisting ofprimary straight-chain and primary branchedchain and secondary groupsand has one of its carbon atoms directly linked to the sulphur atom ofthe sulphonic-acid group, and of a local-anesthetic which is an ester ofa nitrogeneous alcohol and a benzoic acid.

2. A local-anesthetic salt as set forth in claim 1, in which the esteris cocaine.

3. A local-anesthetic salt as set forth in claim 1, in which the esteris procaine.

4. A local-anesthetic salt as set forth in claim 1, in which the esteris 'y- [2-methyl-piperidinol- 15 propyl benzoate.

HORACE A. SHONLE.

